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Staging, treatment, and surveillance of locoregional Merkel cell carcinoma

Staging, treatment, and surveillance of locoregional Merkel cell carcinoma
Authors:
Patricia Tai, MB, BS, DMRT, FRCR, FRCPC
Song Youn Park, MD
Paul T Nghiem, MD, PhD
Ann W Silk, MD, MS
Section Editors:
June K Robinson, MD
Michael B Atkins, MD
Deputy Editor:
Melinda Yushak, MD, MPH
Literature review current through: Jan 2024.
This topic last updated: Aug 10, 2023.

INTRODUCTION — Merkel cell carcinoma (MCC) is a rare, aggressive, cutaneous malignancy that predominantly affects older adults with light skin types and has a high propensity to metastasize.

The staging work-up, management, and surveillance of locoregional MCC are discussed here. The clinical features and initial diagnosis of MCC and the management of metastatic MCC are reviewed separately.

●(See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma".)

●(See "Treatment of recurrent and metastatic Merkel cell carcinoma".)

INITIAL EVALUATION — Once a tumor biopsy has confirmed the diagnosis of MCC, the following evaluation and initial management are suggested. The diagnostic clinical and histopathologic features of a primary MCC tumor are discussed separately. (See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma", section on 'Diagnosis'.)

Physical examination — The initial evaluation of a patient with MCC should include a complete examination of the skin and regional lymph nodes, with appropriate evaluation of any detected abnormalities. The clinical features of MCC are discussed separately. (See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma", section on 'Clinical features'.)

Imaging studies — For all patients with a confirmed diagnosis of MCC, we obtain initial imaging to assess for metastatic disease with either:

●whole-body positron emission tomography (PET) with fluorodeoxyglucose (18F-FDG) combined with axial imaging (either computed tomography [CT] or magnetic resonance imaging [MRI])

or

●contrast-enhanced CT of the chest, abdomen, and pelvis; a CT of the neck should also be obtained in patients with a head and neck primary tumor.

MRI of the brain with contrast may be obtained if the patient has neurologic symptoms (eg, headache, nausea/vomiting, visual difficulties, weakness, or sensory loss) to assess for the presence of central nervous system (CNS) metastases. Because CNS metastases are rare in MCC, we do not routinely order this imaging study for asymptomatic patients.

Patients with MCC are at high risk for metastatic disease to the regional lymph nodes and distant organs. Baseline imaging can identify patients with a higher stage of disease who would benefit from a different treatment approach [1-6]. Imaging studies are also obtained if metastatic disease is suspected by physical examination. The management of metastatic MCC is discussed separately. (See "Treatment of recurrent and metastatic Merkel cell carcinoma".)

In one observational series, baseline imaging detected occult metastatic disease in 13 percent of patients who presented without suspicious physical examination findings (eg, palpable adenopathy) [5]. In this same study, PET-CT detected a higher disease stage more often than CT alone (17 versus 7 percent respectively).

Merkel cell polyomavirus serology — We obtain serologies (antibody titers) for Merkel cell polyomavirus (MCPyV) oncoproteins (small tumor antigen) within three months of initial treatment. A baseline determination of MCPyV serology can be used to reflect subsequent changes in MCC tumor burden [7-10] and determine posttreatment surveillance. For example, patients who are MCPyV-oncoprotein-seronegative at diagnosis are at increased risk of recurrence and may benefit from more intensive surveillance using radiologic imaging [11,12]. (See 'Posttreatment surveillance' below.)

Patients on immunosuppression — If clinically possible, immunosuppressive therapy should be minimized prior to initiating treatment for MCC because immunosuppression is a negative prognostic factor for MCC. The clinician who manages the patient's immunosuppressive therapy should be consulted to determine if appropriate dose reductions or discontinuation of such agents are clinically possible. (See 'Immunosuppression' below.)

STAGING WORK-UP AND MANAGEMENT

General approach — Once the initial evaluation is completed, patients with a biopsy-confirmed primary MCC should proceed with a staging work-up of the primary tumor, lymph nodes, and distant metastases, which is important for both treatment planning and prognosis [13]. (See 'Staging' below.)

●Metastatic disease – Patients with metastatic (stage IV) disease (table 1A and table 1B) have distant metastases to the skin, subcutaneous tissue, lymph nodes, or other visceral sites that are detected on clinical evaluation and/or imaging studies. Patients with biopsy-confirmed metastatic disease typically do not receive further staging evaluation of the primary tumor or lymph nodes and are evaluated for systemic therapy. (See "Treatment of recurrent and metastatic Merkel cell carcinoma".)

●Locoregional disease – Patients with locoregional MCC have no clinical or radiographic evidence of metastatic disease and can be assigned a clinical stage (table 1A). Most patients with resectable disease also receive further pathologic staging evaluation of the primary tumor (via surgical resection (algorithm 1) and lymph nodes (via sentinel lymph node [SLN] evaluation, nodal biopsy, and/or lymph node dissection (algorithm 2 and algorithm 3)) (table 1B).

For most patients with locoregional disease, some initial treatment overlaps with the staging evaluation. The treatment of MCC may include surgery, radiation therapy, and/or systemic therapy. Multidisciplinary evaluation is necessary, with input from dermatology, surgery, medical oncology, and radiation oncology. Patients should be encouraged to enroll in clinical trials, where available (www.clinicaltrials.gov).

Clinically negative regional lymph nodes

Sentinel lymph node biopsy — For most patients with clinically negative regional lymph nodes (ie, no evidence of regional lymph node involvement on physical exam or imaging) and no metastatic disease, we obtain SLN mapping and biopsy, including immunohistochemistry, prior to or in conjunction with (ie, same surgical setting) definitive therapy of the primary tumor (algorithm 3) [12,14]. This specific sequence is necessary because the opposite (definitive treatment of the primary tumor prior to SLN biopsy) would disrupt the lymphatic drainage from the primary tumor and result in a false-negative SLN biopsy. The technique for SLN biopsy, which is widely used in patients with melanoma, is discussed separately. (See "Evaluation and management of regional nodes in primary cutaneous melanoma".)

The following concerns and exceptions to SLN biopsy exist:

●SLN biopsy may be obtained for primary tumors arising in the head and neck region. However, the SLN biopsy may be less accurate because of the variable lymphatic drainage to multiple nodal basins (eg, locating SLN may fail as the radioactive isotope does not move to lymph nodes, or false-negative SLN biopsies may be seen due to discordant lymphatic drainage). The management of patients with a head and neck primary MCC is discussed below. (See 'Head and neck lesions' below.)

●Some clinicians do not perform SLN mapping and biopsy in patients with a primary tumor size ≥2 cm on exam and clinically negative nodes, since elective radiation therapy (RT) to the regional lymph nodes may be indicated due to the high risk of lymph node metastasis. (See 'Sentinel lymph node not assessed' below.)

The results of a SLN biopsy provide important prognostic information and help guide further treatment. In an observational study from the National Cancer Database (NCDB) of 9387 patients with MCC, a negative SLN biopsy was associated with improved five-year overall survival (OS) compared with a positive SLN biopsy (56 versus 40 percent) [15].

Primary tumor — Patients who have completed an SLN biopsy may proceed with definitive treatment of their primary tumor, which is discussed in further detail below. (See 'Management of primary tumor' below.)

Management of lymph nodes after sentinel node biopsy — In patients with clinically negative nodes, treatment of the regional lymph nodes is based on the results of the SLN biopsy (algorithm 3). (See 'Negative sentinel lymph node' below and 'Positive sentinel lymph node' below and 'Sentinel lymph node biopsy' above.)

The management of patients with clinically negative lymph nodes whose SLN is not assessed is also discussed below. (See 'Sentinel lymph node not assessed' below.)

Negative sentinel lymph node — For patients with a negative SLN biopsy who have one or more risk factors for nodal recurrence, we suggest elective RT to the regional lymph nodes rather than observation. In this setting, elective RT is administered at a dose of 46 to 50 Gy [12]. For patients with no risk factors for nodal recurrence, we offer surveillance of the regional lymph nodes. (See 'Posttreatment surveillance' below.)

Risk factors for nodal recurrence in patients with clinically negative lymph nodes include:

●Chronic immunosuppression. (See 'Immunosuppression' below.)

●Possible false-negative SLN biopsy result due to anatomic, technical, or histologic factors – This could occur if the patient underwent wide local excision of the primary tumor prior to SLN biopsy; had a prior history of lymph node excision or nodal lymphoma; had multiple SLN basins, such as a head and neck or midline trunk MCC (see 'Head and neck lesions' below); or if confirmatory immunohistochemistry was not properly performed on the SLN biopsy due to technical issues or limited available tissue.

A negative SLN biopsy does not preclude the risk of a subsequent regional recurrence. A retrospective study of 721 patients with MCC included a subgroup of 518 patients with clinically negative lymph nodes who underwent SLN biopsy. Among this subgroup, the false-negative rate for an SLN biopsy (as defined by a subsequent regional recurrence) was 17 percent [16].

Positive sentinel lymph node — For patients with a positive SLN biopsy, either definitive RT to the regional lymph nodes or completion lymph node dissection (CLND) are appropriate options. Since RT and CLND are similarly effective in clearing the nodal bed in this population, selection of therapy is based upon institutional experience, patient preference, and the potential risks and toxicities of each treatment approach, which are discussed separately. (See "Technique of axillary lymph node dissection", section on 'Complications' and "Radiation therapy techniques in cancer treatment", section on 'Radiation side effects' and "Clinical manifestations, prevention, and treatment of radiation-induced fibrosis".)

Patients with a positive SLN biopsy who receive definitive RT to the lymph nodes are treated at a dose of 50 to 56 Gy [12].

For patients who are treated with CLND, the findings on postoperative pathology determine the need for further adjuvant therapy.

●For patients who have a single involved node and no extracapsular extension, we suggest surveillance rather than adjuvant RT.

●For those who have multiple involved nodes and/or extracapsular extension, we suggest adjuvant RT to the lymph nodes rather than surveillance. (See 'Adjuvant radiation therapy (regional lymph nodes)' below.)

Chronic T-cell immunosuppression is a risk factor for disease recurrence and an indication to receive nodal RT. In most patients with immunosuppression, we prefer CLND followed by adjuvant RT because outcomes (such as recurrence-free survival) for definitive RT alone are frequently disappointing in this population [17]. However, definitive RT to the regional lymph nodes is an option for patients who wish to avoid the potential toxicities of combination therapy, after a thorough risk-benefit discussion about omitting CLND with the clinician.

Approximately one-third of patients with clinically negative lymph nodes will have positive SLN biopsies [16,18,19]. Most observational studies demonstrate similar outcomes for recurrence and survival with either CLND or RT [19-21]. In one observational study, 163 patients with locoregional MCC and positive SLN were offered CLND or definitive RT, based on perioperative risk. At median follow-up of approximately two years, there was no statistically significant difference in five-year MCC-specific (71 versus 64 percent), disease-free (52 versus 61 percent), nodal recurrence-free (76 versus 91 percent), and distant recurrence-free survival (65 versus 75 percent) between the two treatment arms [19].

In another observational study of 71 patients with MCC and positive SLN biopsy, the rates of distant metastases and OS were similar for those treated with CLND, RT, or a combination of both treatments. However, the combination was associated with more complications such as surgical site infections and symptomatic lymphedema [21]. (See "Technique of axillary lymph node dissection", section on 'Complications'.)

Sentinel lymph node not assessed — For most patients whose SLN is not assessed, we suggest elective RT to the regional lymph nodes rather than observation. For such patients who are at risk for subclinical disease, RT is administered at a dose of 46 to 50 Gy [12]. Observation of the lymph nodes is an appropriate alternative for select patients who do not undergo SLN biopsy due to comorbidities and have a primary tumor at low risk for recurrence or metastasis (≤1 cm with no lymphovascular invasion).

For patients who do not undergo nodal evaluation (either with SLN biopsy or lymph node dissection), elective RT to the regional lymph nodes reduces relapse risk, but studies have failed to demonstrate an OS benefit. In patients with a primary tumor ≤1 cm who do not receive any elective regional lymph node treatment, the rate of recurrent nodal disease is at least 17 percent [22,23]. However, in one randomized study of patients with stage I MCC, elective RT to the lymph nodes reduced regional recurrence rates but did not improve progression-free survival or OS compared with observation [23]. (See 'Adjuvant radiation therapy (regional lymph nodes)' below.)

Clinically evident regional lymph nodes

Lymph node biopsy — All patients with clinically evident regional lymph nodes (ie, regional lymph node involvement on physical exam or imaging) and no distant metastases should undergo biopsy confirmation of the involved lymph node prior to definitive treatment of the primary tumor (algorithm 2). Available biopsy techniques include fine needle aspirate, core needle biopsy, or excisional biopsy. If the fine needle aspirate or core needle biopsy of the suspicious node is performed and results are negative or nondiagnostic, an excisional nodal biopsy should be performed to definitively assess for disease involvement [24].

Primary tumor — Patients who have completed their lymph node biopsy may proceed with definitive treatment of their primary tumor, which is discussed in further detail below. (See 'Management of primary tumor' below.)

Management of clinically evident lymph nodes after nodal biopsy — In patients with clinically evident lymph nodes, management of the regional lymph nodes is determined by the biopsy results of the suspicious lymph node (algorithm 2).

Positive nodal biopsy — For patients with clinically evident, biopsy-confirmed nodal disease that is resectable, we suggest therapeutic lymph node dissection rather than definitive RT alone. Patients who undergo lymph node dissection and have multiple involved nodes and/or extracapsular extension on postoperative pathology should be evaluated for adjuvant RT to the lymph nodes. (See 'Adjuvant radiation therapy (regional lymph nodes)' below.)

An alternative approach to lymph node dissection is limited excision of the involved lymph node(s) followed by regional RT to the intervening lymphatics (60 to 66 Gy), provided that the radiation field size is not too large or morbid [25].

Definitive RT to the lymph nodes is an appropriate alternative for patients on chronic immunosuppression, unresectable lymph nodes, or those with significant comorbidities who cannot tolerate surgery to the lymph nodes, including nodal excision under local anesthesia [20,26]. In this setting, definitive RT is administered at a dose of 60 to 66 Gy [12].

In patients with MCC and clinically evident lymph nodes, there are no randomized trials comparing surgical resection with RT alone and available observational data are limited. More aggressive therapy with therapeutic lymph node dissection (with adjuvant RT as indicated) may be necessary since increasing nodal involvement (including clinically evident lymph nodes) is generally associated with a worse prognosis [15,27-30]. In observational studies that included patients with clinically evident lymph nodes, surgical resection was associated with improved [31] or similar OS [32] compared with RT alone. In contrast, observational studies of patients treated with definitive RT alone (without surgical excision of the clinically evident nodal disease) suggest local control rates of approximately 75 to 85 percent [20,26,32-34]. Of note, interpretation of these observational studies may be limited by selection bias based on the chosen therapy.

The role of neoadjuvant and adjuvant systemic therapy in patients with clinically positive lymph nodes is not established. Patients interested in this approach may be enrolled in clinical trials, where available (www.clinicaltrials.gov). (See 'Adjuvant systemic therapy' below and 'What is the role of neoadjuvant immunotherapy?' below.)

Negative nodal biopsy — For most patients whose physical exam or imaging suggests regional lymph node involvement, but whose excisional nodal biopsy demonstrates no evidence of disease involvement, we suggest surveillance of the regional lymph nodes rather than radiation therapy. (See 'Posttreatment surveillance' below.)

However, patients with risk factors for nodal recurrence should be evaluated for RT to the lymph nodes. Risk factors include chronic T-cell immunosuppression or possible false-negative nodal biopsy due to anatomic, technical, or histologic factors. If gross disease is suspected, definitive RT is administered at a dose of 60 to 66 Gy.

Unconfirmed nodal status or indeterminate biopsy — For patients with clinically evident lymph nodes that cannot be confirmed by appropriate pathologic examination (with either nodal biopsy or lymph node dissection), we suggest definitive RT to the regional lymph nodes rather than observation. In this setting, definitive RT is administered at a dose of 60 to 66 Gy [12]. (See 'Adjuvant systemic therapy' below.)

Management of primary tumor — Patients who have completed initial nodal staging evaluation may proceed with treatment of the primary tumor. Available initial treatment options include surgery and/or RT. The choice of therapy is based on tumor resectability (algorithm 1).

Resectable disease — For patients with resectable disease and minimal surgical morbidity who are not anticipated to receive adjuvant RT for the primary tumor, we suggest wide local excision of the primary tumor with a margin of at least 1 centimeter rather than a smaller margin, as this approach is associated with improved long-term disease control. (See 'Wide local excision' below.)

After primary resection, the patient should be evaluated for the presence of specific clinicopathologic risk factors for recurrence at the primary tumor bed to determine the need for further adjuvant therapy to the primary tumor. (See 'Adjuvant radiation therapy (primary tumor)' below.)

Wide local excision — For patients who are not anticipated to receive adjuvant RT, the standard initial management of the primary tumor is wide excision with a surgical margin of at least 1 cm of normal-appearing skin [12,14,35,36]. If the margins are close to or involved with tumor, patients should be evaluated for re-excision. Patients whose tumors are unable to be re-excised (eg, due to surgical morbidity or limited due to tumor location) should be evaluated for adjuvant RT. The indications for adjuvant RT to the primary tumor are discussed below. (See 'Adjuvant radiation therapy (primary tumor)' below.)

Most patients who undergo primary tumor resection also receive adjuvant RT. In such patients, wide surgical margins are not always necessary, as observational studies of patients treated with adjuvant RT suggest that surgical margin status (positive or negative) is not associated with different disease-free survival (DFS) [37] or OS [38]. For patients who are anticipated to receive adjuvant RT, we select a surgical margin size that offers complete or near-complete excision of disease, yet is conservative enough to avoid delays in wound healing and initiating RT. We also avoid extensive tissue movement and grafting which could delay initiation of adjuvant RT [24]. (See 'Adjuvant radiation therapy (primary tumor)' below.)

For patients who are not receiving adjuvant RT, achieving wide negative margins with the initial excision is important for long-term disease control [25,32]. As examples:

●In a retrospective analysis of 188 patients with MCC, 48 were patients treated with surgery alone (all of whom had microscopically negative margins). Of those with surgical margins ≤1 cm, 20 percent (7 of 35 patients) developed a local recurrence, whereas none (0 of 13 patients) developed a local recurrence among those with margins >1 cm. In contrast, among 140 patients treated with adjuvant RT, local control was excellent for patients with both large and small surgical margins, even among patients who had microscopically positive margins (1 percent local recurrence for both margin groups) [37].

●In a retrospective observational study of 179 patients with MCC treated with curative intent, the addition of adjuvant RT to narrow excision (<10 mm margin) was associated with a reduction of local recurrence rates (25 versus 5 percent) and was also effective in the presence of microscopic positive margins. Irrespective of whether RT was used or not, the local recurrence rate was 7 percent when the margin size was >10 mm [32].

Mohs micrographic surgery — Mohs micrographic surgery can be used to treat primary MCC located at a site where the cosmetic outcomes are important, such as the face [39]. If an SLN biopsy is to be carried out, it should be performed prior to Mohs surgery as the tumor excision site may interfere with a subsequent node biopsy [24]. (See 'Sentinel lymph node biopsy' above.)

With the Mohs approach, 100 percent of all major borders, including the deep margins, are evaluated histologically. However, adjuvant RT still has a role in preventing locoregional recurrences when Mohs surgery is used since MCC tends to recur beyond pathologically negative margins more often than other skin cancers [39-42]. (See 'Adjuvant radiation therapy (primary tumor)' below.)

Adjuvant radiation therapy (primary tumor) — For patients with a resected primary tumor at high risk for local recurrence, we suggest adjuvant RT to the primary site rather than observation. High-risk features that are indications for adjuvant RT include [43]:

●Primary tumor ≥1 cm in maximum dimension.

●Microscopically positive or limited surgical margins.

●Lymphovascular invasion.

●A head and neck primary. (See 'Clinical and histologic factors' below.)

●An immunocompromised host. (See 'Immunosuppression' below.)

The RT dose required to treat the primary tumor is based upon surgical margins [12]. Following a resection with negative margins, a total RT dose of 50 to 56 Gy is generally adequate for patients at significant risk for residual subclinical disease. A dose of 56 to 60 Gy is administered for those with microscopically positive resection margins, and a dose of 60 to 66 Gy is administered for those with grossly positive margins where further resection is not possible. Either conventional or short-course hypofractionated RT can be used, as both RT schedules have similar rates of in-field locoregional relapse and disease-specific survival [43].

We do not routinely administer adjuvant chemoradiation after surgical resection of the primary tumor, and the decision to offer it should be individualized. Data obtained prior to the era of immune checkpoint inhibitors are mixed for the efficacy of adjuvant chemoradiation, with some observational studies demonstrating an OS benefit [44] while others did not [45]. Adjuvant chemoradiation also resulted in increased toxicity such as grade ≥3 radiation dermatitis or arterial occlusion [46]. Chemotherapy is also immunosuppressive, which could negatively impact disease control. (See "Radiation dermatitis" and "Radiation therapy techniques in cancer treatment", section on 'Radiation side effects'.)

MCC is a radiosensitive malignancy. RT is used as an adjuvant treatment after surgery to prevent recurrence in the primary tumor bed. Although there are no randomized trials supporting the role of adjuvant RT, observational studies suggest that adjuvant RT decreases the rate of locoregional recurrence and improves OS [32,44,47,48]. As an example, one observational study from the NCDB of 6908 patients with MCC included a subgroup of 4843 patients without evidence of lymph node involvement (stage I or II (table 1A-B)). Within this subgroup, adjuvant RT was associated with significantly improved OS (hazard ratio [HR] 0.71, 95% CI 0.64-0.80) [48].

Unresectable disease

Definitive RT (primary tumor) — Definitive radiation therapy (RT) to the primary tumor is appropriate for patients with locoregional disease that is unresectable or at risk for significant surgical morbidity (such as cosmetic or functional defects [25]), nonsurgical candidates (eg, older adults or those with significant co-morbidities), or those who decline surgery.

Patients receiving definitive RT alone to the primary tumor receive higher doses of radiation (60 to 66 Gy) compared with the doses of RT used in the adjuvant setting for completely resected disease [12]. Either conventional or short-course hypofractionated RT can be used, as both RT schedules have similar rates of in-field locoregional relapse and disease-specific survival [43].

Definitive RT and surgical resection have not been directly compared in randomized trials. Observational studies of definitive RT in unresectable disease suggest similar DFS and OS compared with resectable disease treated with surgery followed by RT [49]. However, definitive RT only achieves an in-field disease control rate between 75 and 88 percent, and systemic relapses can still occur [25,33,34,50].

Other approaches — In patients with disease that is unresectable or at risk for surgical morbidity, the use of neoadjuvant immunotherapy is discussed below. (See 'What is the role of neoadjuvant immunotherapy?' below.)

The role of definitive chemoradiation (CRT) to the primary site is controversial, and there are no randomized studies directly comparing definitive CRT to definitive RT in this population.

SPECIAL CONSIDERATIONS

Head and neck lesions — For patients with a primary MCC arising in the head and neck region, our approach to treatment of the primary tumor and regional lymph nodes is as follows:

●Primary tumor – For patients whose primary tumor is treated with surgical resection, we suggest the addition of adjuvant radiation therapy (RT) to the primary tumor site rather than surgery alone, as this approach is associated with reduced risk of recurrence and improved overall survival (OS).

For those with a primary tumor that is unresectable or at high risk for surgical morbidity, definitive RT is an appropriate alternative. (See 'Management of primary tumor' above.)

●Regional lymph nodes – For patients with head and neck primary tumors and clinically negative nodes, we typically offer sentinel lymph node biopsy, but the accuracy of this test is limited. The lymphatics from primary tumors in this region can variably drain to multiple nodal basins, and there is a higher chance of technical failure of sentinel lymph node (SLN) biopsy [16,51-54]. Another option is to offer patients elective nodal RT, after a risk-benefit discussion of the potential toxicities of RT to multiple nodal basins [55]. Patients who decline elective nodal RT can be observed but are at high risk for recurrence. (See 'Sentinel lymph node biopsy' above.)

For patients with clinically positive, biopsy-confirmed nodal disease, we also use RT (either as adjuvant or definitive therapy) to treat in-transit lymphatics and regional lymph nodes. (See 'Clinically evident regional lymph nodes' above and 'Adjuvant radiation therapy (regional lymph nodes)' below.)

The management of MCC arising in the head and neck region is a unique problem. A primary head and neck tumor is a poor prognostic factor for recurrent or metastatic disease compared with tumors arising from other sites [12,56]. It is also particularly difficult to achieve a wide resection with adequate surgical margins for tumors arising in this region.

Although randomized clinical trials are not available, observational data suggest that the addition of adjuvant RT to surgically resected head and neck tumors improves local and regional disease control [51-53,57]. As examples, in an observational study of 46 patients with low-risk head and neck MCC patients treated with surgery, postoperative (adjuvant) RT was associated with a lower risk of local recurrence versus no postoperative RT (0 versus 26 percent) [58]. In another observational study of 4815 patients with MCC of the head and neck region from the National Cancer Database (NCDB), postoperative RT was associated with improved OS compared with surgery alone (hazard ratio [HR] 0.80, 95% CI 0.70-0.92) [44].

The role of adjuvant therapy is not established in head and neck MCC, and further data are necessary. (See 'Adjuvant systemic therapy' below.)

Unknown primary — The management of patients with an unknown primary tumor should follow that for patients with an identifiable primary tumor and other identifiable sites of disease (clinically positive lymph nodes and/or distant metastases). (See 'Clinically evident regional lymph nodes' above and "Treatment of recurrent and metastatic Merkel cell carcinoma".)

Among patients presenting with clinically detectable lymph nodes at the time of MCC diagnosis (stage III (table 1A)), one-third to one-half of patients do not have an identifiable primary tumor (stage IIIA) [59]. In cases where the primary tumor site is unknown, the primary tumor most likely regressed due to immune surveillance as these patients show markedly stronger immune responses across multiple parameters [59]. It is unlikely that the tumor arose within the lymph node itself, since MCC tumor cells in the lymph node have extensive ultraviolet-induced deoxyribonucleic acid (DNA) mutations and are most likely of cutaneous origin [59].

Observational series suggest that patients with an unknown primary, regional nodal disease and no evidence of distant metastases have better outcomes (with approximately one-half the risk of disease progression) compared with those with a primary cutaneous site in addition to clinically positive lymph nodes [59-63]. As an example, an observational series of 321 patients with MCC included a subset of 38 patients (12 percent) who presented with an unknown primary and nodal disease but no evidence of distant metastases [63]. Among this cohort of patients, median recurrence-free survival and OS were 35 and 104 months, respectively. This study did not have comparative data for patients with a known primary. However, based on another observational study from the NCDB (figure 1B), the median survival those with an unknown primary is almost twice as long than that of node-positive patients with a known primary (3.5 versus 2 years for pathologic stage IIIB tumors) [15]. (See 'Stage' below.)

Adjuvant radiation therapy (regional lymph nodes) — For patients treated with completion lymph node dissection (CLND) who have multiple involved nodes and/or extracapsular extension, we suggest adjuvant RT to the lymph nodes rather than observation. Adjuvant RT in this setting is administered at a dose of 50 to 60 Gy [12]. Clinicians who offer adjuvant RT should also discuss with patients the risks of combining surgery and RT, such as lymphedema, fibrosis, and subsequent functional impairment.

The role of adjuvant RT following complete lymph node dissection has not been definitively established by randomized trials. However, observational studies suggest that adjuvant RT after lymph node dissection decreases the rate of locoregional recurrence and improves OS in patients with high-risk disease [32,44,47,48,64,65]. In one observational study of patients with locally advanced MCC treated with primary resection, the addition of adjuvant RT was associated with improved disease-free survival (DFS) and disease-specific survival in patients with high-risk disease (extranodal extension, two or more positive lymph nodes, or bulkier lymph nodes) [64]. In another study, adjuvant RT confers a survival benefit when the treated lymph node ratio (positive to resected lymph nodes) was greater than 0.215 [66].

Regardless of whether RT is used as an adjuvant or definitive treatment, it is important to treat all regional lymphatics to avoid a recurrence in untreated regions. Some providers use a 5 cm margin to cover the surgical bed for definitive or adjuvant RT [67,68]. As an example, one study (Trans-Tasman Radiation Oncology Group 96:07) evaluating the use of chemoradiation in high-risk MCC used a 3 to 5 cm margin for RT. In addition, if the nodal region was within 20 cm of the primary tumor, the draining lymph nodes were treated in the same field as the primary tumor to reduce the risk of in-transit recurrence [45,46].

Adjuvant systemic therapy

●Adjuvant chemotherapy – The role of adjuvant chemotherapy in patients with resected MCC is uncertain and/or controversial. Although there are no randomized trials, retrospective studies performed prior to the era of immune checkpoint inhibitors suggest no OS benefit for adjuvant chemotherapy [44,48].

●Adjuvant immunotherapy – Although adjuvant immunotherapy for resected MCC is under investigation in clinical trials, it is not used in standard clinical practice. The use of immune checkpoint inhibitors for metastatic MCC is discussed separately. (See "Treatment of recurrent and metastatic Merkel cell carcinoma".)

In an open-label, phase II trial, patients with any stage, completely resected with or without adjuvant radiotherapy-treated MCC were randomly assigned to receive one year of adjuvant nivolumab or surveillance. The 24-month DFS rate with nivolumab was 84 percent compared with 73 percent with surveillance (HR 0.58, 95% CI 0.30-1.12). Overall survival data are immature. Adverse events (grade 3 to 4) occurred in 42 percent with nivolumab and 11 percent with surveillance. More data are needed before routine clinical use of adjuvant immunotherapy in MCC. Ongoing randomized trials continue to assess its efficacy and safety [69].

What is the role of neoadjuvant immunotherapy? — The role of neoadjuvant immunotherapy in the management of patients with MCC is not established and remains under investigation. Neoadjuvant immunotherapy may potentially decrease the extent of necessary surgery or the need for adjuvant RT in patients with a good pathologic response at the primary tumor site and/or regional lymph nodes. While data suggest pathologic complete response (pCR) in approximately one-half of patients [70], additional studies are required to confirm these results.

●Nivolumab – Nivolumab was evaluated in the neoadjuvant setting in a phase I/II study (CheckMate 358). In this study of 39 patients with resectable MCC, surgical resection specimens were obtained after two doses of nivolumab (240 mg on days 1 and 15) [70]. Among the 36 patients who underwent surgery, 17 patients (47 percent) achieved a pCR. Among 33 radiographically evaluable patients, 18 (55 percent) had tumor reductions greater than 30 percent. At a median follow-up of 20.3 months, recurrence-free survival significantly correlated with pCR and radiographic response at the time of surgery. No patient with a pCR had tumor relapse during observation.

STAGING — The eighth edition American Joint Committee on Cancer (AJCC) staging system provides important information for both management and prognosis of patients with MCC [71]. Patients may be assigned a pathologic stage (table 1B) once staging work-up of the primary tumor and lymph nodes is completed.

Based on the eight edition AJCC staging system, MCC staging is assigned based upon tumor, node, and metastasis assessment. These stages can be summarized as follows (table 1A and table 1B):

●Stage I – Primary tumors ≤2 cm in maximum dimension (T1), without evidence of regional lymph node involvement.

●Stage II – Primary tumors >2 cm (T2 or T3) or a primary tumor with invasion into bone, muscle, fascia, or cartilage (T4), without evidence of lymph node involvement. Stage II is further divided into two subgroups based upon the size and depth of invasion of the primary tumor.

●Stage III – Any primary tumor with in-transit metastasis or regional lymph node disease. Pathologic stage III is divided into subgroups based upon the extent of in-transit or regional lymph node involvement.

●Stage IV – Metastasis beyond the regional lymph nodes, regardless of the status of the primary tumor and regional nodes.

POSTTREATMENT SURVEILLANCE — Patients with locoregional MCC who have completed definitive therapy should have frequent follow-up because of the high rates of recurrent disease. Follow-up should be individualized according to risk factors and potential therapeutic options. Our approach to posttreatment surveillance is consistent with guidelines from the National Comprehensive Cancer Network [12].

Frequency of follow-up — As over 90 percent of patients recur within three years [72], they should be followed every three to six months for three years and then every 6 to 12 months thereafter. A physical examination should be performed at every visit, with special emphasis on total-body skin examination and palpation of lymph nodes, given the high frequency of skin and nodal recurrences.

Imaging studies — We obtain imaging studies in patients at high-risk for recurrent or metastatic disease. High-risk patients include those with suspected recurrent or metastatic disease based on surveillance evaluation, immunosuppressed patients, and those definitively treated for clinically positive lymph nodes or other metastatic sites not detected on sentinel lymph node biopsy.

Surveillance imaging options include:

●whole-body fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)-CT with axial imaging (either CT or MRI)

or

●contrast-enhanced CT of the chest, abdomen, and pelvis; a CT of the neck should also be obtained in patients with head and neck primary tumors.

●A contrast-enhanced MRI of the brain may be offered to evaluate for central nervous system metastases in patients with neurologic symptoms (headache, visual difficulties, nausea, vomiting, weakness, or sensory loss).

In one observational study, 18F-FDG PET-CT detected unsuspected recurrences in 33 percent of patients with a lesion-based sensitivity, specificity, and accuracy of 92, 93, and 93 percent, respectively [73]. Those with positive disease on 18F-FDG PET/CT within one year of definitive treatment had significantly worse overall survival (OS). After adjustment for stage, an increased risk of death was associated with a higher maximum standardized uptake value (hazard ratio [HR] for one unit = 1.17) and with a higher number of positive lesions on 18F-FDG PET-CT (HR for one additional lesion = 1.60).

Merkel cell polyomavirus serology — We obtain a Merkel cell polyomavirus (MCPyV)-oncoprotein antibody test every three months while the patient remains at risk for MCC recurrence (typically up to approximately five years). If the titer increases more than 30 percent from the previous value, an imaging study is warranted to evaluate possible recurrence. This surveillance approach is consistent with guidelines from the National Comprehensive Cancer Network guidelines for MCC [12]. (See 'Merkel cell polyomavirus serology' above.)

Changes in the titer of antibodies that recognize MCPyV oncoproteins reflect alterations in a patient's MCC tumor burden [7-10,74]. For seropositive patients, MCPyV-oncoprotein antibody titers may be a useful component of ongoing surveillance, as a rising titer can be an early indicator of recurrence [11,75]. Additionally, for patients who do not have recurrent disease, titers are expected to decrease significantly within three months of successful treatment of MCC [11]. A combination of the MCPyV-oncoprotein antibody test and imaging studies can help guide surveillance.

In an analysis of 260 patients with MCC who had a positive MCPyV-oncoprotein antibody test, the positive predictive value of recurrence was 99 percent (eg, fraction of patients with rising titers that had or soon developed clinically evident MCC recurrence) and the negative predictive value was 99 percent (eg, fraction of patients with stable or declining titers who did not have detectable recurrent disease) [76]. In some cases, the antibody test outperformed imaging by identifying recurrences before they were detectable on imaging studies.

Co-occurring malignancies — MCC is associated with an increased incidence of other skin cancers (melanoma, basal and squamous cell carcinoma) and keratinocyte malignancies, due to the common risk factor sun exposure. Patients with MCC are also at risk for hematologic malignancies that are associated with immunosuppression, such as multiple myeloma and chronic lymphocytic leukemia. Patients with treated MCC who are under surveillance should also be evaluated for the potential development of such malignancies. (See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma", section on 'Epidemiology'.)

PROGNOSIS — The prognosis of patients with MCC is influenced by various clinical and pathologic features. (See 'Posttreatment surveillance' above and "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma", section on 'Pathogenesis'.)

Stage — The stage (or extent) of disease at presentation is the most important prognostic factor in patients with MCC [15,18,77,78]. The stage of disease is represented by the American Joint Committee on Cancer (AJCC) staging system (table 1A and table 1B). (See 'Staging' above.)

Overall survival (OS) of MCC based on disease extent was demonstrated by an observational study from the National Cancer Database (NCDB) in 9387 patients with MCC (figure 1A-C) [15].

●Local disease – Among the patients who had local disease without evidence of regional lymph node involvement or metastatic disease at initial presentation (65 percent of the total cohort), five-year OS was 55.6 percent. Patients with higher tumor (T) stage of the primary lesion had progressively lower five-year OS, as follows:

•T1 (≤2 cm) – 55.8 percent

•T2-3 (>2 to 5, >5 cm) – 41.1 percent

•T4 (invasion of fascia or deeper tissues) – 31.8 percent

●Regional disease – Among the patients who had regional lymph node involvement without disseminated metastatic disease (26 percent of the total cohort), five-year OS was 35.4 percent. OS within specific subgroups were as follows (figure 1C):

•Occult disease (detected by sentinel lymph node [SLN] biopsy or regional lymph node dissection) – Five-year OS of 39.7 percent.

•Clinically detected regional lymph node involvement – Five-year OS of 26.8 percent.

•In-transit metastases – Three-year OS of 41.4 percent (figure 1C).

●Unknown primary – Among the patients with an unknown primary tumor and lymph node metastasis (3.6 percent of the total cohort), five-year OS was 42.2 percent.

●Distant metastases – Among patients with distant metastatic disease at initial presentation (8 percent), five-year OS was 13.5 percent.

Of note, disease-specific survival (DFS) by stage was not evaluated in this study. Clinicians should be aware that, in the older adults affected by MCC, a significant proportion of deaths captured by OS are not due to MCC. In addition, the OS data in this study was obtained prior to the routine use of immunotherapy. Other studies are variable for stage-specific recurrence rates, DFS, and OS.

Other prognostic factors

Merkel cell polyomavirus tumor antigen — Tumors that are positive Merkel cell polyomavirus (MCPyV) large tumor antigen have a favorable prognosis, including reduced risk of recurrence and improved disease-specific survival [11,79,80]. MCPyV antigen expression is also associated with expression of the retinoblastoma protein. MCPyV DNA-positive tumors are preferentially located on the limbs and metastasize less frequently compared with MCPyV DNA-negative MCCs [81]. (See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma", section on 'Merkel cell polyomavirus'.)

Immunosuppression — T-cell immunosuppression (eg, HIV infection, solid organ transplant, or hematologic malignancies such as chronic lymphocytic leukemia or lymphoma) is associated with decreased MCC-specific survival and OS [82-85]. The type of immunosuppression also impacts survival outcomes. Observational data in MCC patients suggest that solid organ transplant is associated with lower OS compared with other types of immunosuppression [84].

Clinical and histologic factors — Other clinical and histologic factors associated with a favorable prognosis in MCC include:

●Female sex

●Younger age at diagnosis

●Absence of comorbid conditions [86,87]

●Tumor-infiltrating lymphocytes [88,89]

Factors associated with a poor prognosis include:

●Head and neck primary site [75]

●Lymphovascular invasion [27,90]

●p63 expression [91,92]

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Non-melanoma skin cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Initial evaluation – The initial evaluation of the patient with a biopsy-confirmed diagnosis of Merkel cell carcinoma (MCC) includes a complete examination of the skin and regional lymph nodes, imaging studies to assess for metastatic disease, Merkel cell polyomavirus (MCPyV) serologies, and minimization of immunosuppressive therapy. (See 'Initial evaluation' above.)

●Staging work-up and treatment – For most patients with locoregional MCC, some initial treatment overlaps with the staging evaluation. Multidisciplinary evaluation is necessary. (See 'Staging work-up and management' above and 'General approach' above.)

●Clinically negative regional lymph nodes – For most patients with clinically negative regional lymph nodes (ie, no evidence of regional lymph node involvement on physical exam or imaging) and no metastatic disease, we obtain sentinel lymph node (SLN) mapping and biopsy, including immunohistochemistry, prior to or in conjunction with (ie, in the same surgical setting as) definitive therapy of the primary tumor (algorithm 3). (See 'Clinically negative regional lymph nodes' above.)

•Negative SLN – For patients with a negative SLN biopsy who have one or more risk factors for nodal recurrence, we suggest elective radiation therapy (RT) to the regional lymph nodes rather than observation (Grade 2C). Risk factors include chronic immunosuppression or a possible false-negative SLN biopsy result due to anatomic, technical, or histologic factors. (See 'Negative sentinel lymph node' above.)

For patients with no risk factors for nodal recurrence, we offer surveillance of the regional lymph nodes.

•Positive SLN – For patients with a positive SLN biopsy, either definitive RT to the regional lymph nodes or completion lymph node dissection (CLND) are appropriate options. Since RT and CLND are similarly effective in clearing the nodal bed in this population, selection of therapy is based upon institutional experience, patient preference, and the potential risks and toxicities of each treatment approach. (See 'Positive sentinel lymph node' above.)

For patients with a positive SLN biopsy who are treated with CLND, findings on postoperative pathology determine the need for further adjuvant therapy.

-For patients who have a single involved node and no extracapsular extension, we suggest surveillance rather than adjuvant RT (Grade 2C).

-For those who have multiple involved nodes and/or extracapsular extension, we suggest adjuvant RT to the lymph nodes rather than surveillance (Grade 2C). (See 'Adjuvant radiation therapy (regional lymph nodes)' above.)

•SLN not assessed – For most patients whose SLN is not assessed, we suggest elective RT to the regional lymph nodes rather than observation (Grade 2C). Observation of the lymph nodes is an appropriate alternative for select patients who do not undergo SLN biopsy due to comorbidities and have a primary tumor at low risk for recurrence or metastasis (≤1 cm with no lymphovascular invasion). (See 'Sentinel lymph node not assessed' above.)

●Clinically evident regional lymph nodes – All patients with clinically evident regional lymph nodes (ie, regional lymph node involvement on physical exam or imaging) and no distant metastases should undergo biopsy confirmation of the involved lymph node prior to definitive treatment of the primary tumor (algorithm 2). (See 'Clinically evident regional lymph nodes' above.)

•Positive nodal biopsy – For patients with clinically evident, biopsy-confirmed nodal disease that is resectable, we suggest therapeutic lymph node dissection rather than definitive RT alone or limited nodal resection followed by radiation (Grade 2C). (See 'Positive nodal biopsy' above.)

-For patients treated with therapeutic lymph node dissection who have multiple involved nodes and/or extracapsular extension, we suggest adjuvant RT to the lymph nodes rather than observation (Grade 2C). (See 'Adjuvant radiation therapy (regional lymph nodes)' above.)

-Definitive RT to the lymph nodes is an appropriate alternative for patients on chronic immunosuppression, unresectable lymph nodes, or those with significant comorbidities who cannot tolerate surgery to the lymph nodes. (See 'Positive nodal biopsy' above.)

•Negative nodal biopsy – For most patients whose physical exam or imaging suggest regional lymph node involvement, but whose excisional nodal biopsy demonstrates no evidence of disease involvement, we suggest surveillance of the regional lymph nodes rather than radiation therapy (Grade 2C). However, patients with risk factors for nodal recurrence (chronic immunosuppression or possible false-negative nodal biopsy) should be evaluated for definitive RT to the lymph nodes. (See 'Negative nodal biopsy' above.)

•Unconfirmed nodal status or indeterminate biopsy – For patients with clinically evident lymph nodes that cannot be confirmed by appropriate pathologic examination (with either nodal biopsy or lymph node dissection), we suggest definitive RT to the regional lymph nodes rather than observation (Grade 2C). (See 'Unconfirmed nodal status or indeterminate biopsy' above.)

●Management of the primary tumor – Patients who have completed initial nodal staging evaluation may proceed with treatment of the primary tumor (algorithm 1). (See 'Management of primary tumor' above.)

•Resectable disease – For patients with resectable disease and minimal surgical morbidity who are not anticipated to receive adjuvant RT for the primary tumor, we suggest wide local excision of the primary tumor with a margin of at least 1 centimeter rather than a smaller margin (Grade 2C), as this approach is associated with improved long-term disease control. For patients who are anticipated to receive adjuvant RT, we select a surgical margin size that offers complete or near-complete excision of disease, yet is conservative enough to avoid delays in wound healing and initiating RT. (See 'Resectable disease' above.)

-Adjuvant radiation therapy (primary tumor) – For patients with a resected primary tumor at high-risk for local recurrence, we suggest adjuvant RT to the primary site rather than observation (Grade 2C). High-risk features include primary tumor ≥1 cm, microscopically positive or limited surgical margins, lymphovascular invasion, a head and neck primary, and an immunocompromised host. (See 'Adjuvant radiation therapy (primary tumor)' above.)

•Unresectable disease – Definitive RT to the primary tumor is appropriate for patients with locoregional disease that is unresectable or at risk for significant surgical morbidity, non-surgical candidates, or those who decline surgery. (See 'Unresectable disease' above.)

●Staging – MCC staging is assigned based upon the tumor, node, and metastases American Joint Committee on Cancer (AJCC) staging system (table 1A and table 1B). (See 'Staging' above.)

●Surveillance – Following initial definitive therapy, patients with MCC should have frequent follow-up due to the high rates of recurrent disease. (See 'Posttreatment surveillance' above.)

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  85. Tarantola TI, Vallow LA, Halyard MY, et al. Prognostic factors in Merkel cell carcinoma: analysis of 240 cases. J Am Acad Dermatol 2013; 68:425.
  86. Tai PT, Yu E, Tonita J, Gilchrist J. Merkel cell carcinoma of the skin. J Cutan Med Surg 2000; 4:186.
  87. McEvoy A, Lachance K, Hippe D. Addressing the missing components for appropriate surveillance of Merkel cell carcinoma patients: Detailed recurrence data and an integrated risk analysis approach. J Invest Dermatol 2019; 139(5):S99.
  88. Paulson KG, Iyer JG, Tegeder AR, et al. Transcriptome-wide studies of merkel cell carcinoma and validation of intratumoral CD8+ lymphocyte invasion as an independent predictor of survival. J Clin Oncol 2011; 29:1539.
  89. Butala AA, Jain V, Reddy VK, et al. Impact of Tumor-Infiltrating Lymphocytes on Overall Survival in Merkel Cell Carcinoma. Oncologist 2021; 26:63.
  90. Andea AA, Coit DG, Amin B, Busam KJ. Merkel cell carcinoma: histologic features and prognosis. Cancer 2008; 113:2549.
  91. Asioli S, Righi A, de Biase D, et al. Expression of p63 is the sole independent marker of aggressiveness in localised (stage I-II) Merkel cell carcinomas. Mod Pathol 2011; 24:1451.
  92. Stetsenko GY, Malekirad J, Paulson KG, et al. p63 expression in Merkel cell carcinoma predicts poorer survival yet may have limited clinical utility. Am J Clin Pathol 2013; 140:838.
Topic 7609 Version 72.0

References

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3 : 18F-FDG PET provides high-impact and powerful prognostic stratification in the staging of Merkel cell carcinoma: a 15-year institutional experience.

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8 : T-cell responses to oncogenic merkel cell polyomavirus proteins distinguish patients with merkel cell carcinoma from healthy donors.

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11 : Viral oncoprotein antibodies as a marker for recurrence of Merkel cell carcinoma: A prospective validation study.

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36 : Association Between Surgical Margins Larger Than 1 cm and Overall Survival in Patients With Merkel Cell Carcinoma.

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63 : Merkel cell carcinoma of unknown primary origin.

64 : Regional lymph node irradiation in locally advanced Merkel cell carcinoma reduces regional and distant relapse and improves disease-specific survival.

65 : Postoperative radiotherapy in stage I-III Merkel cell carcinoma.

66 : Lymph node ratio predicts efficacy of postoperative radiation therapy in nonmetastatic Merkel cell carcinoma: A population-based analysis.

67 : The important role of radiation treatment in the management of Merkel cell carcinoma.

68 : Effect of radiotherapy dose and volume on relapse in Merkel cell cancer of the skin.

69 : Adjuvant immunotherapy with nivolumab versus observation in completely resected Merkel cell carcinoma (ADMEC-O): disease-free survival results from a randomised, open-label, phase 2 trial.

70 : Neoadjuvant Nivolumab for Patients With Resectable Merkel Cell Carcinoma in the CheckMate 358 Trial.

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73 : 18F-FDG PET/CT for Posttreatment Surveillance Imaging of Patients with Stage III Merkel Cell Carcinoma.

74 : Positive correlation between Merkel cell polyomavirus viral load and capsid-specific antibody titer.

75 : Positive correlation between Merkel cell polyomavirus viral load and capsid-specific antibody titer.

76 : 590 Detecting Merkel cell carcinoma recurrence using a blood test: Outcomes from 774 patients

77 : Merkel Cell Carcinoma Outcomes: Does AJCC8 Underestimate Survival?

78 : Recurrence and Mortality Risk of Merkel Cell Carcinoma by Cancer Stage and Time From Diagnosis.

79 : Merkel cell polyomavirus infection, large T antigen, retinoblastoma protein and outcome in Merkel cell carcinoma.

80 : Polyomavirus-Negative Merkel Cell Carcinoma: A More Aggressive Subtype Based on Analysis of 282 Cases Using Multimodal Tumor Virus Detection.

81 : Clinical factors associated with Merkel cell polyomavirus infection in Merkel cell carcinoma.

82 : Effect of host, tumor, diagnostic, and treatment variables on outcomes in a large cohort with Merkel cell carcinoma.

83 : Merkel Cell Carcinoma Analysis of Outcomes: A 30-Year Experience.

84 : Merkel cell carcinoma patients with solid organ transplant or hematologic malignancy: Demographics, survival, and prognosticators.

85 : Prognostic factors in Merkel cell carcinoma: analysis of 240 cases.

86 : Merkel cell carcinoma of the skin.

87 : Addressing the missing components for appropriate surveillance of Merkel cell carcinoma patients: Detailed recurrence data and an integrated risk analysis approach

88 : Transcriptome-wide studies of merkel cell carcinoma and validation of intratumoral CD8+ lymphocyte invasion as an independent predictor of survival.

89 : Impact of Tumor-Infiltrating Lymphocytes on Overall Survival in Merkel Cell Carcinoma.

90 : Merkel cell carcinoma: histologic features and prognosis.

91 : Expression of p63 is the sole independent marker of aggressiveness in localised (stage I-II) Merkel cell carcinomas.

92 : p63 expression in Merkel cell carcinoma predicts poorer survival yet may have limited clinical utility.

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